Benign prostatic hypertrophy (BPH) is one of the most common diseases in adult males. Histological evidence of BPH has been found in more than 40% of men in their fifties and almost 90% of men in their eighties. The disease results from the accumulation of non-malignant nodules arising in a small region around the proximal segment of the prostatic urethra which leads to an increase in prostate volume. If left untreated, BPH can result in acute and chronic retention of urine, renal failure secondary to obstructive uropathy, serious urinary tract infection and irreversible bladder decompensation.
The majority of men over fifty years of age are considered to have some urinary symptoms attributable to BPH. Treatment of BPH accounts for about 1.7 million physician office visits and more than 300,000 prostatectomies annually in the Unites States alone, resulting in total annual estimated charges of more than five billion dollars (Guess, Epidem. Rev. 1992 14:131-136; Holtgrewe, Urology 1995 46(Suppl3A): 23-25).
There are two main courses of treatment for patients diagnosed with BPH. For over 50 years, transurethral resection of the prostate has been the standard treatment for men with an enlarged prostate and obstructive symptoms (Lepor, J. Urol. 1990 143:533-537). However, this has not been entirely satisfactory. Morbidity associated with the surgical approach includes clot retention, excessive bleeding, bladder neck contracture, impotence, retrograde ejaculation and infection and an increase in long term mortality (Roos et al. N. Engl. J. Med. 1989 320:1120-1124). The other approach is pharmacological. Alpha-adrenergic antagonists have been shown to block the adrenergic receptors in the prostatic capsule and bladder neck (Lepor, Urology 1993 42:483-501). This results in a loss of smooth muscle tone and a concomitant decrease in the resistance to urine flow. This leads to an improvement in symptoms but does not affect the prostate volume. Another compound, finasteride is a potent competitive inhibitor of the enzyme 5a-reductase (involved in the conversion of testosterone to DHT). Clinical studies have demonstrated that patients treated with this drug exhibited significant reductions in prostate volume, measured by transrectal ultrasound. Continuous therapy with finasteride maintained a 25% reduction in prostate volume during three years of administration in over 50% of patients with no loss of efficacy suggesting that the progress of the disease had been halted (Rittmaster, N. Eng. J. Med. 1994 330:120-125, Gormley et al. N. Eng. J. Med. 1992 327:1184-1191).
However, information concerning the factors which initiate and promote the development of BPH, the mechanisms by which BPH alters voiding mechanisms, and definitive diagnostic criteria to establish the role of BPH in clinical changes is lacking. Despite the high prevalence of BPH, the clinical diagnostic criteria are not very specific and no single BPH case definition has gained wide acceptance for use in epidemiological studies. A three-fold definition of BPH is provided by Roylance et al. Biomed. and Pharmacol. 1995 49:332-338. First, BPH is characterized by microscopic evidence of hyperplasia. Second, a clinical definition of BPH is based on a medical history which includes information on symptoms and a digital rectal examination. However, this information actually defines prostatism rather than urologically confirmed disease. Third, not all patients with BPH diagnosed clinically have urologically confirmed disease; other conditions such as urethral stricture, dysfunction of the bladder neck and prostate also give rise to symptoms of prostatism. A diagnosis of BPH on prostate size alone can be misleading because only a weak correlation exists between prostate size and symptoms of outflow. Thus, while the pathologic diagnostic criteria for BPH are relatively specific, clinical diagnostic criteria are much less specific.
The only marker currently available for BPH is PSA (prostate specific antigen) (Wang et al. Prostate 1996 28:10-16, Lee and Oesterling Sem. in Surg. Oncol. 1995 11:23-25). PSA levels are elevated in many patients with BPH. However, elevated levels of PSA also are found in diseases such as prostate cancer and thus can not be used to distinguish among the various types of pathology. Accordingly, there is a need for a specific marker and method for the unambiguous diagnosis of BPH.
Clearly, there is a need for factors that are specific markers for prostate disease, particularly BPH and their roles in dysfunction and disease. There is a need, therefore, for identification and characterization of such factors that specific markers for prostate disease, particularly BPH, and which can play a role in preventing, ameliorating or correcting dysfunctions or diseases.